In the last decade, a number of molecules have become available for the treatment of HIV-infected individuals. Therapeutic regimens based on the combination of reverse transcriptase inhibitors and protease inhibitors have been shown to reduce plasma HIV-1 RNA to undetectable levels in patients, increase CD4 cell counts and delay progression toward AIDS.
HIV reverse transcriptase (RT) inhibitors that target the polymerase activity of RT, can be subdivided into two classes of potent agents: nucleosides that terminate viral DNA synthesis, such as zidovudine (AZT), dideoxyinosine (ddI) and dideoxycytidine (ddC), and nonnucleoside analogs that bind to a hydrophobic cavity adjacent to the polymerase active site such as nevapirine (1). However, these agents present several limitations, including toxicity which sometimes requires patient's treatment to be suspended (2), and the emergence of resistant strains which are generated through the exceptionally high rate of mutagenesis of RNA viruses (3-6). For example, resistance to zidovudine is conferred by amino acid changes that appear in an orderly fashion: a K70R mutation first, followed by T125F/Y, M41L, D67N, and 1(219Q mutations (7,8). Similarly, other mutations correlate with resistant phenotype to other RT inhibitors (9). Thus, the development of novel compounds that are active against multidrug-resistant HIV variants is urgently needed.
An interesting feature of HIV-1 RT is that the dimeric form of the enzyme consisting of two polypeptides p66 and p51, is absolutely required for its catalytic activities (10). Based on the x-ray crystallographic structure of HIV-1 RT, it was previously demonstrated that the first interaction between p66 and p51 occurs in a Tryptophan (Trp)-rich hydrophobic cluster located in the connection subdomain of the two subunits and is followed by a conformational change involving the thumb and the finger subdomains of p51 as well as the RNase-H and the palm subdomains of p66 (11).